Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Abstract

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in ~10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data suggest a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

JAK-STAT Signaling Enables Lineage Plasticity-driven AR Targeted Therapy Resistance

“…One example of the lineage plasticity-driven resistance occurs in mCRPC with concurrent loss-of-function of TP53 and RB1, which is then accompanied by ectopic activation of SOX2 (9,10). Similar cases of lineage plasticity have been observed in mCRPC carrying various genomic and transcriptional aberrations, including but not limited to aberrations in PTEN, FOXA1, BRN2, SOX11, N-MYC, PEG10, CHD1, REST, and BRG1 (7,(11)(12)(13)(14)(15)(16)(17)(18). This lineage plasticity-driven resistance in mCRPC parallels examples documented in EGFR-mutant lung adenocarcinoma, ERpositive breast cancers, and BRAF-mutant melanoma (19)(20)(21)(22).…”

“…Emerging evidence demonstrates that lineage plasticity represents an important mechanism for conferring targeted therapy resistance in various cancers, particularly prominent in cancers where the molecular target of therapies are the lineage-specific survival factors, including ERpositive breast cancer, EGFR-mutant lung cancer, BRAF-mutant melanoma, and AR-dependent PCa (7,(9)(10)(11)(12)(13)(14)(15)(16)(19)(20)(21)(22). In the case of PCa, however, it is not fully understood whether the differentiated luminal tumor cells acquire lineage plasticity-driven resistance through reverting back (de-differentiating) to a multi-lineage, stem cell-like state and then re-differentiating to alternative lineages, or through direct trans-differentiation to a distinctively new lineage (10,18,49).…”

“…Various genetic and transcriptional aberrations have been connected to the acquisition of lineage plasticity in PCa, including, but not limited to, the aberrations of PTEN, BRN2, FOXA1, N-Myc, PEG10, CHD1, REST, and BRG1 (7,(11)(12)(13)(14)(15)(16). Interestingly, many of those cases involve the "hijacking" of stem-like, pluripotency, or epigenetic regulation programs, such as SOX2, SOX11, EZH2, and the SWI/SNF complex (9,10,(13)(14)(15)18).…”

“…Various genetic and transcriptional aberrations have been connected to the acquisition of lineage plasticity in PCa, including, but not limited to, the aberrations of PTEN, BRN2, FOXA1, N-Myc, PEG10, CHD1, REST, and BRG1 (7,(11)(12)(13)(14)(15)(16). Interestingly, many of those cases involve the "hijacking" of stem-like, pluripotency, or epigenetic regulation programs, such as SOX2, SOX11, EZH2, and the SWI/SNF complex (9,10,(13)(14)(15)18). Although the role of JAK-STAT signaling pathway in regulating cell fate decision, stem cell self-renewal, and multilineage differentiation has been well documented (23)(24)(25), its potential function in mediating lineage plasticity-driven AR therapy resistance remained largely unclear.…”

Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers

“…In line with these findings in neuroblastoma, recent work from the Rubin laboratory has identified the chromatin remodeling mSWI/SNF complexes as a potential regulator of SCPCa lineage plasticity (Cyrta et al, 2020). Specialized assemblies of the SWI/ SNF complex with distinct functions are observed at different stages of embryonic development and tissue maturation (Ho et al, 2009(Ho et al, , 2011.…”